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Acute inhibition of excessive mitochondrial fission after myocardial infarction prevents long-term cardiac dysfunction.

Authors: Disatnik, Marie-Hélène  Ferreira, Julio C B  Campos, Juliane Cruz  Gomes, Kátia Sampaio  Dourado, Paulo M M  Qi, Xin  Mochly-Rosen, Daria 
Citation: Disatnik MH, etal., J Am Heart Assoc. 2013 Oct 8;2(5):e000461. doi: 10.1161/JAHA.113.000461.
Pubmed: (View Article at PubMed) PMID:24103571
DOI: Full-text: DOI:10.1161/JAHA.113.000461


BACKGROUND: Ischemia and reperfusion (IR) injury remains a major cause of morbidity and mortality and multiple molecular and cellular pathways have been implicated in this injury. We determined whether acute inhibition of excessive mitochondrial fission at the onset of reperfusion improves mitochondrial dysfunction and cardiac contractility postmyocardial infarction in rats.
METHODS AND RESULTS: We used a selective inhibitor of the fission machinery, P110, which we have recently designed. P110 treatment inhibited the interaction of fission proteins Fis1/Drp1, decreased mitochondrial fission, and improved bioenergetics in three different rat models of IR, including primary cardiomyocytes, ex vivo heart model, and an in vivo myocardial infarction model. Drp1 transiently bound to the mitochondria following IR injury and P110 treatment blocked this Drp1 mitochondrial association. Compared with control treatment, P110 (1 µmol/L) decreased infarct size by 28 ± 2% and increased adenosine triphosphate levels by 70+1% after IR relative to control IR in the ex vivo model. Intraperitoneal injection of P110 (0.5 mg/kg) at the onset of reperfusion in an in vivo model resulted in improved mitochondrial oxygen consumption by 68% when measured 3 weeks after ischemic injury, improved cardiac fractional shortening by 35%, reduced mitochondrial H2O2 uncoupling state by 70%, and improved overall mitochondrial functions.
CONCLUSIONS: Together, we show that excessive mitochondrial fission at reperfusion contributes to long-term cardiac dysfunction in rats and that acute inhibition of excessive mitochondrial fission at the onset of reperfusion is sufficient to result in long-term benefits as evidenced by inhibiting cardiac dysfunction 3 weeks after acute myocardial infarction.

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CRRD Object Information
CRRD ID: 12738206
Created: 2017-01-30
Species: All species
Last Modified: 2017-01-30
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.